Abstract This work will involve the development of an invasive gene drive system in the Zika, Chikungunya, and Dengue mosquito, Ae. aegypti, a major vector of human insect-borne disease known to annually infect up to 500 million people worldwide, hospitalizing over a million, and killing approximately 25,000. The current approaches used for mosquito disease prevention, including vector suppression by environmental modification, insecticides, and anti-inflammatory drugs, are simply insufficient. The replacement of wild mosquito populations with genetically modified individuals that are engineered to be ?disease resistant? should provide a sustainable, long-term, method for disease prevention. However, the transgenes that mediate disease refractoriness are unlikely to confer an overall fitness benefit to insects that carry them. Additionally, wild populations are large, partially reproductively isolated, and dispersed over wide areas. Therefore, population replacement requires a gene drive mechanism in order to spread linked cargo genes, mediating disease refractoriness, through wild pathogen transmitting populations. Here I propose to ?resurrect? the historical concept of using reciprocal chromosomal translocations to spread disease refractory genes into wild pathogen transmitting mosquito populations. While this approach was rigorously attempted in the past, it was ultimately completely abandoned, due to elevated fitness costs resulting from the technologies used to generate the translocation strains, in addition to the inabilities to link genes for disease resistance to the chromosomal break-points. Importantly, recent advancements in genetic engineering and synthetic biology allow for these historical problems to be entirely overcome. Furthermore, translocation-mediated gene drive systems are threshold-dependent and thus have several attractive features important for social and scientific acceptance for wild transgenic releases: the systems are species specific; zero horizontal spread between species; minimal ecological impact in contrast to insecticides; robust and unbreakable with a inexorable linkage of the selfish genetic element with its cargo; complete transgene removal from wild population can be carried out if desired. Therefore, this project will utilize cutting-edge applied synthetic biology principals to engineer reciprocal chromosomal translocations at precise locations in Ae. aegypti (Aim-1). Once translocation-bearing strains are established, these will be introgressed with wild genetic backgrounds, fitness dynamics will be measured, and small laboratory-scale drive experiments will be executed (Aim-2). Overall, a successful translocation-based population replacement system linked with disease refractory genes will have a significant impact on both human health and the technical capability in which mosquitoes and other insects will be managed in the future. As these systems can be designed in most insects, this innovative approach could also later be engineered in wide range of insect disease vectors, revolutionizing and modernizing the field of insect population control.